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Relapsing diabetes can result from moderately activating mutations in KCNJ11
Anna L Gloyn1, Frank Reimann, Christophe Girard
1Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, USA.
Human Molecular Genetics
|February 19, 2005
Summary
Mutations in KCNJ11, previously linked to permanent neonatal diabetes, can also cause transient neonatal diabetes. This finding suggests a single gene can lead to both remitting and permanent forms of the condition.
Area of Science:
- Genetics
- Endocrinology
- Molecular Biology
Background:
- Neonatal diabetes presents as transient (TNDM) or permanent (PNDM), often considered genetically distinct.
- Chromosome 6q24 abnormalities are the most frequent cause of TNDM.
- KCNJ11 mutations encoding Kir6.2 are the primary cause of PNDM, sometimes with neurological comorbidities.
Purpose of the Study:
- To investigate if KCNJ11 mutations can also cause transient neonatal diabetes (TNDM).
- To identify novel KCNJ11 mutations in TNDM patients lacking 6q24 abnormalities.
- To functionally characterize TNDM-associated KCNJ11 mutations.
Main Methods:
- Genetic analysis of 11 TNDM probands without 6q24 abnormalities.
- Identification and co-segregation analysis of novel KCNJ11 mutations.
- Functional characterization of mutated Kir6.2 channels in Xenopus laevis oocytes.
Main Results:
- Three novel heterozygous KCNJ11 mutations (G53S, G53R, I182V) were identified in TNDM probands.
- These mutations co-segregated with diabetes and were absent in controls.
- Functional studies showed reduced ATP sensitivity for TNDM mutations, less severe than PNDM mutations.
Conclusions:
- KCNJ11 mutations are the first identified genetic cause for both transient and permanent neonatal diabetes.
- A single ion channel defect can manifest as a fluctuating glycemic phenotype.
- The severity of KCNJ11 mutations in vitro correlates with diverse clinical phenotypes.